Welcome to CMC Strategy Forum Latin America 2019 On behalf of the CASSS Board of Directors and the CMC Strategy Forum Global Steering Committee, we would like to extend to you a warm welcome to the fourth meeting of the CMC Strategy Forum Latin America 2019. We are very pleased to have the strong support from ANVISA-Brazilian National Health Surveillance Agency, as well as SINDUSFARMA-Brazilian Union of Pharmaceutical Products Industry in São Paulo and the participation of WHO, Health Canada and Latin America regulatory agencies, as well as the continued support by CASSS and the United States Food and Drug Administration (FDA). The Forum will follow the established model of the CMC Forum series with focus on topics and regulatory updates relevant for Latin America and will feature an opening regulatory session that will include presentations from LATAM regulators, as well as the FDA. The technical sessions will include discussion on: “Post Approval Changes for Biotech Products”, “ICH CTD Structure for Module 3 for Biotech” and “Stability for Biotech Products”. We would like to thank the speakers and the panel members who are giving generously of their time and resources and to you for your attendance. The success of the CMC Strategy Forum Latin America will depend on your active participation in discussing and raising issues pertaining to the development of biologics. We encourage you to participate whole-heartedly in the panel discussions that have been designed to stimulate exchange of ideas and information.

ACKNOWLEDGEMENTS LATIN AMERICA SCIENTIFIC ORGANIZING COMMITTEE Kalinka de Melo Carrijo, ANVISA-Brazilian National Health Surveillance Agency, Brasil Daniela Cerqueira, ANVISA-Brazilian National Health Surveillance Agency, Brasil Carmilia Jiménez Ramirez, Ajinomoto Bio-Pharma Services, USA Joseph Kutza, AstraZeneca, USA Rosana Mastelaro, SINDUSFARMA- Brazilian Union of Pharmaceutical Products Industry in São Paulo, Brasil Ana Padua, Merck Serono S.A., Switzerland Livia Partika, Biogen Idec Brasil Produtos Farmacêuticos, Brasil Thomas Schreitmüller, F. Hoffmann-La Roche Ltd., Switzerland Cecilia Tami, CDER, FDA, USA CMC STRATEGY FORUM GLOBAL STEERING COMMITTEE Siddharth Advant, Celgene Corporation, USA Daniela Cerqueira, ANVISA-Brasilian National Health Surveillance Agency, Brasil Yasuhiro Kishioka, PMDA-Pharmaceutical and Medical Devices Agency, Japan Junichi Koga, Daiichi Sankyo Co., Ltd., Japan Steven Kozlowski, CDER, FDA, USA Rohin Mhatre, Biogen, USA Anthony Mire-Sluis, AstraZeneca., USA Wassim Nashabeh, F. Hoffmann-La Roche Ltd., USA (Chair) Ilona Reischl, BASG-Federal Office for Safety in Health Care, Austria Anthony Ridgway, Health Canada, Canada Nadine Ritter, Global Biotech Experts, LLC, USA Thomas Schreitmüller, F. Hoffmann-La Roche Ltd., Switzerland Mark Schenerman, CMC Biotech-MAS Consulting, USA Karin Sewerin, BioPharmaLinx AB, Sweden Chikako Torigoe, CBER, FDA, USA

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CMC Strategy Forum Latin America 2019 Scientific Program Summary

Tuesday, 12 March 2019

08:00 – 09:00 Registration in the ANVISA Auditorium Foyer 09:00 – 09:15 CASSS Welcome and Introductory Comments in the ANVISA Auditorium Nadine Ritter, CASSS Vice President, Global Biotech Experts, LLC 09:15 – 09:45 CMC Strategy Forum Latin America 2019 Welcome and Introductory

Comments - Overview of Biotech Products in Brasil in the ANVISA Auditorium Dr. William Dib, President, ANVISA-Brazilian National Health Surveillance Agency Dr. Nelson Mussolini, Executive President, SINDUSFARMA- Brazilian Union of Pharmaceutical Products Industry in São Paulo

Recent Trends in the Regulation of Biotechnology Products in Latin America

In the ANVISA Auditorium Session Chairs: Daniela Marreco Cerqueira, ANVISA and Ana Padua, Merck Serono S.A.

09:45 – 10:10 ANVISA – Current Biologics Regulatory Scenario in Brasil Carolina Damas Rocha Zarate Blades, ANVISA-Brazilian National Health

Surveillance Agency, Brasil 10:10 – 10:35 Trends in the Development of Biological and Biosimilar Products in

Argentina Claudia Saidman, ANMAT-National Administration of Medicines, Food and Medical Technology, Argentina

10:35 – 11:00 Recent Trends in the Regulation of Biotechnology Products in Paraguay

Q.F. Julio Cesar Rolón Esteche, , MSPBS-Ministry of Public Health and Social Welfare, Paraguay

11:00 – 11:30 AM Break in the Foyer 11:30 – 11:55 Recent Trends in the Regulation of Biotechnology Products in Bolivia Eliana Caballero Vedia, AGEMED, Ministry of Health, Bolivia 11:55 – 12:20 Recent Trends in the Regulation of Biotechnology Products in Uruguay Isabel Slepak, Ministry of Public Health, Uruguay 12:20 – 13:30 Buffet Lunch in the Foyer

Tuesday, 12 March continued… 13:30 – 14:45 Panel Discussion – Questions and Answers Carolina Damas Rocha Zarate Blades, ANVISA-Brazilian National Health

Surveillance Agency, Brasil Eliana Caballero Vedia, AGEMED, Ministry of Health, Bolivia Julio Rolón, MSPBS-Ministry of Public Health and Social Welfare, Paraguay

Claudia Saidman, ANMAT-National Administration of Medicines, Food and Medical Technology, Argentina

Isabel Slepak, Ministry of Public Health, Uruguay 14:45 – 15:15 PM Break in the Foyer

ICH CTD Structure for Module 3 for Biotech In the ANVISA Auditorium

Session Chairs: Carmilia Jiménez Ramirez, Ajinomoto Bio-Pharma Services and Joseph Kutza, AstraZeneca

15:15 – 15:25 Introduction 15:25 – 15:50 Implementation of the ICH CTD Structure for Module 3 for Biotech: Health

Canada’s Experience Hugo Hamel, Health Canada, Canada 15:50 – 16:15 Advantages and Challenges with Using CTD Module 3 for CMC Information Flávia Firmino, Pfizer, Inc., Brasil 16:15 – 16:40 Analyical Elements of Module 3 for Biopharm Products: Beyond S.4 and P.5 Nadine Ritter, Global Biotech Experts, USA 16:40 – 17:00 Mini-break in the Foyer 17:00 – 18:00 Panel Discussion - Questions and Answers

Flávia Firmino, Pfizer, Inc., Brasil Hugo Hamel, Health Canada, Canada Livia Partika, Biogen Idec Brasil Produtos Farmacêuticos, Brasil Nadine Ritter, Global Biotech Experts, USA

18:00 Adjourn Day One 18:30 – 20:30 Networking Reception at the Meliá Brasil 21 in Encontro III

Wednesday, 13 March 2019

Regulations for Post Approval Changes of Biotherapeutics - Global Developments and Opportunities for the Region

In the ANVISA Auditorium Session Chairs: Rosana Mastelaro, SINDUSFARMA and Thomas Schreitmüller, F. Hoffmann-La

Roche Ltd. (representing FIFARMA) 09:00 – 09:20 Why We Need Effective LCM Regulatory Systems Now and Even More in

the Future – An Introduction Thomas Schreitmüeller, F. Hoffmann-La Roche Ltd., Switzerland (representing FIFARMA)

09:20 – 09:40 The WHO Guidelines on Procedures and Data Requirements for Changes to Approved Biotherapeutic Products: Evaluation Principles in the New Guidelines (Main Body) - HyeNa Kang, WHO-World Health Organization, Geneva, Switzerland

09:40 – 10:00 The WHO Guidelines on Procedures and Data Requirements for Changes to Approved Biotherapeutic Products: How to Use WHO Guidelines on Post-approval Changes (Appendices) Hugo Hamel, Health Canada, Canada

10:00 – 10:20 Reviewing Process of the Stability and Post-approval Change Regulations for Biological Products in Brasil Carolina Damas Rocha Zarate Blades, ANVISA-Brazilian National Health Surveillance Agency, Brasil

10:20 – 10:50 AM Break in the Foyer 10:50 – 11:10 Case Study: How Can We Use the WHO Guidelines on Procedures and Data

Requirements for Changes to Approved Biotherapeutic Products in Real-life Examples?

Maria Cristina Mota Pina, AbbVie, Inc., USA 11:10 – 11:30 Post Approval Changes Regulation in Argentina: Development Phase,

Current Status of Public Consultations and Next Steps Patricia Aprea, ANMAT-National Administration of Medicines, Food and Medical Technology, Argentina

11:30 – 12:30 Panel Discussion – Questions and Answers

Patricia Aprea, ANMAT-National Administration of Medicines, Food and Medical Technology, Argentina Carolina Damas Rocha Zarate Blades, ANVISA-Brazilian National Health Surveillance Agency, Brasil Hugo Hamel, Health Canada, Canada

Wednesday, 13 March continued…

Panel Discussion – Questions and Answers (continued) HyeNa Kang, WHO-World Health Organization, Geneva, Switzerland

Maria Cristina Mota Pina, Abbvie, Inc., USA Thomas Schreitmüeller, F. Hoffmann-La Roche Ltd., Switzerland (representing FIFARMA)

12:30 – 13:30 Buffet Lunch in the Foyer

Stability for Biotechnological Products In the ANVISA Auditorium

Session Chairs: Lori McCaig, Genentech, a Member of the Roche Group and Camilla Santos, Amgen Inc.

13:30 – 13:40 Introduction 13:40 – 14:05 In-use Stability, Correlation with Climatic Zones and Strategies for Post-

approval Changes Kavita Ramalingam Iyer, Merck Sharp & Dohme Corporation., USA

14:05 – 14:30 Applying Science- and Risk-based Stability Strategies Globally: An Industry

Case Study Donnie Pulliam, Biogen, USA 14:30 – 14:55 Post-approval Stability Requirements - Biologics Germán Lastra, Amgen Limited, United Kingdom 15:00 – 15:30 PM Break in the Foyer 15:30 – 15:55 Relevance of Stability Studies on Demonstrating Biosimilarity Laura Giribaldi, Amega Biotech, Argentina 16:00 – 17:00 Panel Discussion – Questions and Answers Carolina Damas Rocha Zarate Blades, ANVISA-Brazilian National Health

Surveillance Agency, Brasil Laura Giribaldi, Amgega Biotech, Argentina Kavita Ramalingam Iyer, Merck Sharp & Dohme Corporation, USA Carmilia Jiménez Ramirez, Ajinomoto Bio-Pharma Services, USA

Joseph Kutza, AstraZeneca, USA Germán Lastra, Amgen Limited, United Kingdom

Donnie Pulliam, Biogen, USA

Wednesday, 13 March continued… 17:00 – 17:45 Recap of Program Summary Slide Presentation

Carmilia Jiménez Ramirez, Ajinomoto Bio-Pharma Services, USA Nadine Ritter, Global Biotech Experts, LLC, USA 17:45 – 18:00 Closing Remarks Thomas Schreitmüller, F. Hoffmann-La Roche Ltd., Switzerland 18:00 Adjournment

Welcome and Introductory Comments CASSS Welcome and Introductory Comments Nadine Ritter, CASSS Vice President Global Biotech Experts, LLC, USA AND CMC Strategy Forum Latin America 2019 Welcome and Introductory Comments – Overview of Biotech Products in Brasil Dr. William Dib, President ANVISA-Brazilian National Health Surveillance Agency Dr. Nelson Mussolini, Executive President SINDUSFARMA- Brazilian Union of Pharmaceutical Products Industry in São Paulo NOTES:

Recent Trends in the Regulation of Biotechnology Products in Latin America

Session Chairs: Daniela Marreco Cerqueira, ANVISA-Brazilian National Health Surveillance Agency and Ana Padua, Merck Serono S.A. In this plenary session, regulators from Argentina, Brazil, Bolivia, Paraguay and Uruguay will provide the status of biotech regulatory framework in their countries including main opportunities and challenges as well as the trends foreseen in the upcoming years. The Latin American countries are evolving to have a structured regulatory framework for Biotherapeutic products. CASSS recognizes the difficulty of handling this challenging environment alone given new technologies/therapies evolving rapidly and patient’s urgency. In this context, the plenary session promotes constructive interactions between regulators and industry to tackle the key factors that prevent patients to receive medicines faster. At the end of this session, regulators and industry should be able to identify areas of mutual collaboration, convergence and work-sharing to improve/accelerate the product registration processes and resources optimization to assist patients better in a healthy and transparent environment. NOTES:

Presenter’s Abstracts ANVISA – Current Biologics Regulatory Scenario in Brasil Carolina Damas Rocha Zarate Blades ANVISA-Brazilian National Health Surveillance Agency, Brasil NOTES:

Trends in the Development of Biological and Biosimilar Products in Argentina Claudia Saidman ANMAT-National Administration of Medicines, Food and Medical Technology, Argentina NOTES:

Recent Trends in the Regulation of Biotechnoloogy Products in Paraguay Q.F. Julio Cesar Rolón Esteche MSPBS-Ministry of Public Health and Social Welfare, Paraguay Antecedents in the regulation of biological medicines in Paraguay. Current legislation. Reference Regulatory Agencies for the country. Technical requirements according to Decree No. 6611/16 (general and specific requirements according to classification of biological medicines). Process of adaptation to the requirements of biological medicines. Current situation in the evaluation of biological medicines. Opportunities and challenges. NOTES:

Recent Trends in the Regulation of Biotechnology Products in Bolivia Eliana Caballero Vedia AGEMED, Ministry of Health, Bolivia NOTES:

Recent Trends in the Regulation of Biotechnology Products in Uruguay Isabel Slepak Ministry of Public Health, Uruguay NOTES:

Recent Trends in the Regulation of Biotechnology Products in Latin America

Panel Members: Carolina Damas Rocha Zarate Blades, ANVISA-Brazilian National Health Surveillance Agency, Brasil Eliana Caballero Vedia, AGEMED, Ministry of Health, Bolivia Julio Rolón, MSPBS-Ministry of Public Health and Social Welfare, Paraguay Claudia Saidman, ANMAT-National Administration of Medicines, Food and Medical Technology, Argentina Isabel Slepak, Ministry of Public Health, Uruguay The following questions will guide the panel discussion:

• Based on your experience, considering that regulatory convergence is the foundation for further collaboration among regulators (reliance), what are the key factors that make regulators to still have country specific requirements?

• Are country specific requirements essential for patient’s safety? What are the reasons behind? • Any trends to reduce countries particularities in the future? • How industry can plan a collaborative role to drive regulatory convergence? • Please share ideas to finally achieve a satisfactory level of regulatory convergence that will really

speed up the approval of high relevant medicines to patients? • Is your country already working in any type of reliance procedure for faster approval of medicines?

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ICH CTD Structure for Module 3 for Biotech Session Chairs: Carmilia Jiménez Ramirez, Ajinomoto Bio-Pharma Services and Joseph Kutza, AstraZeneca Many Health Authorities in Latin America are adopting the ICH CTD format for regulatory submissions. While there are many benefits to using a common technical dossier such as review efficiency, work-sharing among regulators, and time saving for manufacturers who operate globally, there can also be some challenges during the initial use of a new format such as finding data, documents, and commitments. The objective of this session is to specifically cover the content of ICH CTD Module 3. Representatives from regulatory authorities and industry using CTD formatted documents will share their experience and lessons learned on CTD adoption. Panelists will include regulators in the process of adopting the ICH format who will share their challenges and expectations. Together, regulators and industry representatives will discuss the best path forward for the successful implementation of ICH formatted submissions throughout Latin America. Please bring your questions, comments and experiences to date for the discussion period. NOTES:

Presenter’s Abstracts Implementation of the ICH CTD Structure for Module 3 for Biotech: Health Canada's Experience Hugo Hamel Health Canada, Canada Health Canada has been accepting regulatory submissions in CTD format since 2003. As of today, several hundred submissions for biotherapeutic products have been filed in CTD format in Canada. Although the objective of the CTD format is to facilitate the use of a common format for the filing of the regulatory submissions globally, some inconsistencies with respect to the location of information are commonly noted. This presentation will provide an overview of the Health Canada’s experience reviewing Module 3 for biotech products and will highlight the best practices and identify areas for improvement. NOTES:

Advantages and Challenges with Using CTD Module 3 for CMC Information Flávia Firmino Pfizer, Inc., Brasil Although there were challenges initially because it was a new standard, today, adopting CTD is much simpler and swifter given the number of years of global companies and health authorities that have been working under a CTD standardize format. The objective of this session is to provide an overview of the content of ICH CTD Module 3 and the challenges and advantages of using the Common Technical Document (CTD) for product registration purposes. NOTES:

Analyical Elements of Module 3 for Biopharm Products: Beyond S.4 and P.5 Nadine Ritter Global Biotech Experts, LLC, USA Sections S.4 (Drug Substance) and P.5 (Drug Product) contain the descriptions of analytical methods used in the product specifications, and the summary of their method verifications and validations. But numerous additional sections of Module 3 include the analytics applied to biopharm products for characterization, comparability, reference standards, raw materials, excipients, compatibility, leachables, stability, and -for Biosimilars - similarity. This presentation will illustrate the numerous types of analytical methods and data that are described by ICHQM4 to be included in each section of 3.2.S, 3.2.P, along with the Appendix and the Regional sections, for biopharm original and Biosimilar products. NOTES:

ICH CTD Structure for Module 3 for Biotech Panel Members: Flávia Firmino, Pfizer, Inc., Brasil Hugo Hamel, Health Canada, Canada Livia Partika, Biogen Idec Brasil Produtos Farmacêuticos, Brasil Nadine Ritter, Global Biotech Experts, LLC, USA The following questions will guide the panel discussion:

1) Regarding the draft guidance from ANVISA for CTD content a. What have been the most commented topics or input gathered from industry? b. What kind of input/comments have industry leaders provided?

2) Provide examples on how CTD content and format are leveraged in your typical submission? 3) How are regulatory agencies and sponsors enacting plans to convert previously filed dossiers to

CTD format?

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Regulations for Post Approval Changes of Biotherapeutics – Global Developments and Opportunities for the Region

Session Chairs: Rosana Mastelaro, SINDUSFARMA and Thomas Schreitmüller, F. Hoffmann-La Roche Ltd. (representing FIFARMA) Effective life cycle management (LCM) of approved medicinal products is a key activity of regulatory agencies and pharmaceutical industry to ensure sustained supply of state-of-the-art manufactured, safe and efficacious products to patients. While recognition of the importance of LCM is seen on a global basis by more and more national regulatory authorities (NRA) requiring submissions for post-approval technical and label changes. This situation may escalate even further as products and their clinical applications become more complex, their manufacturing sites, process and control system as well as their label are updated more frequently and so the number of post-approval changes will increase. On top it is anticipated that more products will be approved through accelerated pathways responding to unmet needs. This will result in post authorization of clinical and manufacturing development activities and is another key driver for an effective and efficient LCM in an environment which differs very much from the concept of approving the ‘final’ commercial product/data through the initial license. The recently established WHO “guidelines on procedures and data requirements for changes to approved biotherapeutic products”, approved during the session of the WHO expert committee on biological standardization, Geneva, 17 to 20 October 2017, is the key document in solving most if not all issues outlined above with respect to post-approval changes (PACs) for biotherapeutic products (BTPs). Covering the regulation of PACs for BTPs incl. CMC related changes as well as safety and efficacy changes with impact on clinical use and labelling changes, the guideline is providing risk-based categorization of changes (checklists), reporting procedures, and the data requirements to support the proposed changes. In addition, the WHO “guidelines on procedures and data requirements for changes to approved biotherapeutic products” is fully complementary to the currently developed ICHQ12 guideline “TECHNICAL AND REGULATORY CONSIDERATIONS FOR PHARMACEUTICAL PRODUCT LIFECYCLE MANAGEMENT”, for example, in the sense that ICHQ12 with elaborating on established conditions will provide clarity on what is change relevant while the WHO guidance is providing the “how” e.g. how to classify a change and what kind and amount of data are required to justify the regulatory approval. NOTES:

Presenter’s Abstracts Why We Need Effective LCM Regulatory Systems Now and Even More in the Future – An Introduction Thomas Schreitmüeller F. Hoffmann-La Roche Ltd., Switzerland (representing FIFARMA) NOTES:

The WHO Guidelines on Procedures and Data Requirements for Changes to Approved Biotherapeutic Products: Evaluation Principles in the New Guidelines (Main Body) - HyeNa Kang WHO-World Health Organization, Geneva, Switzerland Biotherapeutic products are an increasingly important component of global health care and several WHO guidelines on the regulatory evaluation of these products are available. During international consultations on the development of these WHO guidelines, and also during their implementation, it became clear that there was also a need to develop WHO guidelines for changes to approved biotherapeutic products in order to help address complexity and other challenges associated with the global life-cycle management of such products. In 2014, the 67th World Health Assembly adopted two relevant resolutions: one on promoting access to biotherapeutic products and ensuring their quality, safety and efficacy and the other on regulatory systems strengthening. In support of these resolutions, WHO was requested to provide guidance on how to deal with increasingly complex biotherapeutic products, including similar biotherapeutic products (SBPs). In addition, the 16th International Conference of Drug Regulatory Authorities (ICDRA) recommended that WHO assist Member States in ensuring regulatory oversight throughout the life-cycle of biotherapeutic products. Manufacturing processes are often altered after regulatory approval and medicines can undergo changes during their product life-cycle. Changes are essential for the continual improvement of the manufacturing process and for maintaining state-of-the-art controls of biotherapeutic products, and often need to be implemented after the product has been approved. The WHO guidelines on procedures and data requirements for changes to approved biotherapeutic products were developed to provide guidance to national regulatory authorities (NRAs) and manufacturers on regulating changes to already licensed biotherapeutic products, including biosimilars, in order to assure their continued quality, safety and efficacy, as well as continuity in supply and access. The guidelines were the result of three rounds of international consultations and one informal consultation in 2016 – 2017 and adopted by the WHO Expert Committee on Biological Standardization (ECBS) in Oct 2017. The guidelines note that implementation of new regulations should not affect product supply and access to products. Therefore, NRAs are strongly encouraged to establish requirements that are commensurate with their own regulatory capacity, experience and resources and to apply the concepts of reliance or work sharing or to use collaborative approaches when reviewing post-approval changes. NRAs of countries procuring products are encouraged to consider establishing procedures for the expedited approval of changes based on previous expert review and approval of the same changes by the NRAs of the countries where these products are licensed or based on the decision of a recognized regional regulatory authority. NOTES:

The WHO Guidelines on Procedures and Data Requirements for Changes to Approved Biotherapeutic Products: How to Use WHO Guidelines on Post-approval Changes (Appendices) Hugo Hamel Health Canada, Canada Manufacturing processes are often altered after regulatory approval and medicines can undergo changes during their product life cycle. Changes are essential for the continual improvement of the manufacturing process and for maintaining state-of-the-art controls of biotherapeutic products, and often need to be implemented after the product has been approved. The WHO guidelines on procedures and data requirements for changes to approved biotherapeutic products were developed to provide guidance to national regulatory authorities (NRAs) and manufacturers on regulating changes to already licensed biotherapeutic products, including biosimilars, in order to assure their continued quality, safety and efficacy, as well as continuity in supply and access. While the previous talk given by Dr. Hye-Na Kang will focus on the evaluation principles written in the main body of the guidelines, this presentation will provide an overview on how to use the WHO post-approval changes guidelines with specific examples taken from Appendix 2 and Appendix 3. NOTES:

Reviewing Process of the Stability and Post-approval Change Regulations for Biological Products in Brasil Carolina Damas Rocha Zarate Blades ANVISA-Brazilian National Health Surveillance Agency, Brasil In 2018, the Office of Biological Products started the discussions for the review of the regulatory requirements for stability (Resolution 50/2011) and post-registration of biological products (Resolution 49/2011). One of the objectives of this review process is to seek the harmonization of Anvisa’s legal framework with ICH, WHO and other international guidelines. Regarding the Resolution on Stability the reference guideline is the Q5C ICH and our main objective is to update the procedures and conditions for conducting stability studies of biological products. For the Resolution on post-registration, the draft is being prepared using as main references the following documents:

• WHO: Guidelines on procedures and data requirements for changes to approved biotherapeutic products (2017);

• WHO: Guidelines on procedures and data requirements for changes to approved vaccines (2015);

• Health Canada: GUIDANCE DOCUMENT Post-Notice of Compliance (NOC) Changes: Quality Document - Appendix 3: Quality Post-NOC Changes (Biologics), 2016.

Our goal is moving towards more efficient regulatory systems, promoting access to biological products with quality, safety and efficacy throughout their life-cycle, taking into consideration the Brazilian context. NOTES:

Case Study: How Can We Use the WHO Guidelines on Procedures and Data Requirements for Changes to Approved Biotherapeutic Products in Real-life Examples? Maria Cristina Mota Pina AbbVie, Inc., USA This presentation will focus in the applicability of the guideline using a case study for a complex post approval change. Post-approval changes are part of the life cycle of a product. The case study exemplifies a post-approval change and will assess how the WHO guideline can support the industry when assessing changes, using ICH-CTD nomenclature. NOTES:

Post Approval Changes Regulation in Argentina: Development Phase, Current Status of Public Consultations and Next Steps Patricia Aprea ANMAT-National Administration of Medicines, Food and Medical Technology, Argentina NOTES:

Regulations for Post Approval Changes of Biotherapeutics – Global Developments and Opportunities for the Region

Panel Members: Patricia Aprea, ANMAT-National Administration of Medicines, Food and Medical Technology, Argentina Carolina Damas Rocha Zarate Blades, ANVISA-Brazilian National Health Surveillance Agency, Brasil Hugo Hamel, Health Canada, Canada HyeNa Kang, WHO-World Health Organization, Geneva, Switzerland Maria Cristina Mota Pina, Abbvie, Inc., USA Thomas Schreitmüeller, F. Hoffmann-La Roche Ltd., Switzerland (representing FIFARMA) The following questions will guide the panel discussion:

• Where do we stand with the implementation of the principles on procedures and data requirements for changes to approved biotherapeutic products outlined in the WHO guidance in individual countries and globally?

• What can/should be done to facilitate/accelerate implementation? • What is it you like from the WHO PAC guideline for biotherapeutic products? • What is it you criticize or think should be improved? • The WHO guidance is suggesting very concretely change categorization and respective data

requirements. Do you find this helpful for or it’s rather hindering implementation? • During the consultation period of developing the WHO PAC guidelines, WHO has received several

requests from regulators to develop a template for the annual report of minor changes. What’s the opinion of industry and regulators?

• WHO is also suggesting “new” regulatory tools to be implemented in the context of PAC e.g. the PACMP (Post Approval Change Management Protocol) what are thoughts/is the experience in applying these tools?

• For the first time in a global regulatory document on PAC requirements, reliance based approval procedures are proposed. What is the experience on this, what are thoughts around implementation?

• ICH Q12 is also moving and step 4 is expected soon. What are your thoughts around the links between those two documents?

• What does it mean for implementation e.g. any recommendation around a sequence?

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Stability for Biotechnological Products Session Chairs: Lori McCaig, Genentech, a Member of the Roche Group and Camilla Santos, Amgen Inc. This session will focus on providing an overview and discussion regarding development and management of stability programs for innovators and biosimilars. Development and management of stability programs for biotechnological products require consideration of multiple aspects to confirm suitable long-term storage conditions ensuring proper potency, purity and product quality throughout product shelf life. The supporting data package submitted in regional markets needs to demonstrate product knowledge, clear understanding of the potential degradation pathways, suitable methods with adequate sensitivity to measure product attribute changes, and assurance of product stability through production, storage, transport, distribution and routine handling in the clinic or at the point of administration. ICH Q5C, Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products provides guidance for selection of representative material, experimental design to cover a broad range of product configurations, minimum requirements for assessment of product quality attributes and points to consider for selection of appropriate environmental conditions for the study. Given the complexities described in this guideline, there are opportunities to develop multiple approaches to comply with its requirements. Points to discuss in this session will include appropriate study design for market introduction, post-approval process changes, “lean” approaches to enable faster market approval and for ongoing monitoring, and the relevance of stability to biosimilarity assessments. Perspectives from industry experts from the United States, Europe and Latin America and regulatory agencies will be provided by this session’s panel members. NOTES:

Presenter’s Abstracts In-use Stability, Correlation with Climatic Zones and Strategies for Post-approval Changes Kavita Ramalingam Iyer Merck Sharp & Dohme Corporation., USA NOTES:

Applying Science- and Risk-based Stability Strategies Globally: An Industry Case Study Donnie Pulliam Biogen, USA This presentation will summarize the reduced stability testing post-approval commitment approved by global health authorities for one of Biogen’s products, and the elements of the registration application which supported the approval of this “lean stability” strategy. ICH Q5C encourages the submission of post-approval/post-licensure stability protocols which support elimination of specific test intervals relative to those prescribed in the guidance to achieve marketing authorization. This and other lean stability approaches can help focus more company resources on developing new therapies, while continuing to ensure an appropriate level of quality monitoring for batches representing distributed product in the supply chain. Attendees will also hear about recent industry efforts to encourage the expanded usage of lean stability approaches in pharmaceutical development, registration applications, and post-approval CMC change management. NOTES:

Post-approval Stability Requirements - Biologics Germán Lastra Amgen Limited, United Kingdom By distinguishing between the stability studies required for the establishment of the shelf life and storage conditions for a new drug substance or drug product and those required to support post-approval changes to the manufacture of biological medicinal products, science- and risk-based approaches with a greater emphasis on product knowledge and process and product comparability can be leveraged to enable more timely filing, approval, and implementation of changes. Regional differences in the degree to which these principles are accepted and the application of additional administrative and data requirements can delay and complicate the global implementation of post-approval changes and hamper the timely patient access to medicines. This presentation will consider regional stability requirements for post-approval changes and the impact that they have on single changes and on the roll-out of a sequence of changes. NOTES:

Relevance of Stability Studies on Demonstrating Biosimilarity Laura Giribaldi Amega Biotech, Argentina Forced degradation studies are useful to predict biopharmaceuticals stability and provide information about analytical methods ability to detect degradation products. In addition, they play a key role in establishing biosimilarity. Typical stress tests include degradation factors such as heat, hydrolytic, oxidative, and agitation. The aim of this work was to compare a set of analytical methods for detecting instability of erythropoietin and etanercept during stress conditions. Harsh storage conditions such as low and high pH, temperature, oxidation, freeze-thaw cycles and agitation were evaluated. Samples were analyzed in order to evaluate purity, impurities, post-translational modifications, higher order structure and biological activity. The results demonstrated that a number of analytical techniques were able to detect and characterize various alterations in primary structure, changes in physical stability, binding to a specific target, and biological activity of the studied proteins. Then, biosimilar and reference products were subjected to stress conditions and the evaluation of differences in the relative abundance of degradation products was studied. Overall, the changes that occurred under stress conditions and the degree at which they occurred were similar between AmegaBiotech products and reference products, showing that the degradation pattern was similar in both cases. NOTES:

Stability for Biotechnological Products Panel Members: Carolina Damas Rocha Zarate Blades, ANVISA-Brazilian National Health Surveillance Agency, Brasil Laura Giribaldi, Amgega Biotech, Argentina Kavita Ramalingam Iyer, Merck Sharp & Dohme Corporation, USA Carmilia Jiménez Ramirez, Ajinomoto Bio-Pharma Services, USA Joseph Kutza, AstraZeneca, USA Germán Lastra, Amgen Limited, United Kingdom Donnie Pulliam, Biogen, USA The following questions will guide the panel discussion:

• Are ICH comparability strategies gaining worldwide acceptance as a means to apply established expiry to post-change product, as it will greatly benefit all to utilize a global expiry?

• Is it acceptable to utilize primary lot data (including at clinical/pilot scale) to support the market application, including support for stress studies, such as accelerated storage or temperature cycling, versus validation/commercial lot data?

• Could regulators comment on their local policies to potentially align biologic stability programs to ICH? The industry response to the 2018 ANVISA guidance continues to raise awareness to the need for regulatory convergence.

• What are the expectations / requirements for in-use studies and compatability studies (types of lots, how many needed)?

• How are lean stability approaches used in the development and registration phases of a new product?

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